A5022936068- Viral Infections and Vectors
- interferon and immune responses
- Mosquito-borne diseases and control
- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- SARS-CoV-2 and COVID-19 Research
- Reproductive System and Pregnancy
- Immune Cell Function and Interaction
- RNA regulation and disease
- Long-Term Effects of COVID-19
- COVID-19 Clinical Research Studies
- Pregnancy and preeclampsia studies
- Cytomegalovirus and herpesvirus research
- COVID-19 Impact on Reproduction
- Virology and Viral Diseases
- Erythrocyte Function and Pathophysiology
- RNA Research and Splicing
- Viral Infections and Immunology Research
- Psychology of Development and Education
- Immune Response and Inflammation
- Neuroinflammation and Neurodegeneration Mechanisms
- PARP inhibition in cancer therapy
- Viral Infections and Outbreaks Research
- Child and Adolescent Psychosocial and Emotional Development
- Biochemical and Molecular Research
University of Pennsylvania
2020-2025
California University of Pennsylvania
2021-2024
Philadelphia University
2022
Dana-Farber Cancer Institute
2013-2020
Harvard University
2013-2020
Yale University
2016-2019
Howard Hughes Medical Institute
2018
Harvard University Press
2012
Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, IFN-α/β receptor (IFNAR)-deficient mice highly susceptible to ZIKV infection. Severe restriction placental damage resorption observed after of type IFN knockout (Ifnar1-/-) dams mated wild-type sires, resulting in fetuses functional signaling. The role IFNs limiting or...
There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening human Huh7.5 validates 23 diverse antiviral Extending our studies lung epithelial cells, find that there are major differences drug sensitivity and entry pathways used by SARS-CoV-2 these cells. Entry Calu-3 pH independent...
Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses formulated explain the etiology PASC, including viral persistence, chronic inflammation, hypercoagulability, autonomic dysfunction. Here, we propose mechanism that links all four in single pathway provides actionable insights for therapeutic interventions. We find PASC are associated with...
The strong association of Zika virus infection with congenital defects has led to questions how a flavivirus is capable crossing the placental barrier reach fetal brain. Here, we demonstrate permissive primary human macrophages, commonly referred as Hofbauer cells, and villous fibroblasts. We also cells within context tissue ex vivo using term explants. In addition amplifying infectious usually inaccessible area, putative migratory activities may aid in dissemination Understanding...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, infecting over 43 million people and claiming 1 lives, with these numbers increasing daily. Therefore, there is urgent need to understand the molecular mechanisms governing SARS-CoV-2 pathogenesis, immune evasion, disease progression. Here, we show that can block IRF3 NF-κB activation early during virus infection. We also identify viral proteins NSP1 NSP13 interferon via distinct...
Integration is essential for HIV-1 replication, and the viral integrase (IN) protein an important therapeutic target. Allosteric IN inhibitors (ALLINIs) that engage dimer interface at binding site host lens epithelium-derived growth factor (LEDGF)/transcriptional coactivator p75 are emerging class of small molecule antagonists. Consistent with inhibition a multivalent drug target, ALLINIs display steep antiviral dose–response curves ex vivo. multimerize concordantly block its assembly DNA in...
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly neurological dysfunction. ZIKV persists in the semen months after acute viremic phase humans. To further understand consequences of persistence males, we infected Ifnar1-/- mice via subcutaneous injection a pathogenic but nonlethal strain. replication within testes even clearance from blood, with interstitial,...
ABSTRACT During virion maturation, HIV-1 capsid protein assembles into a conical core containing the viral ribonucleoprotein (vRNP) complex, thought to be composed mainly of RNA and nucleocapsid (NC). After infection, is reverse transcribed double-stranded DNA, which then incorporated host chromosomes by integrase (IN) catalysis. Certain IN mutations (class II) antiviral drugs (allosteric inhibitors [ALLINIs]) adversely affect resulting in virions that contain “eccentric condensates,”...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of DNA (mtDNA) activation innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these effects, we challenged mice expressing human...
The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity HIV-1 integration. However, a significant residual preference for integration into active genes persists Psip1 (the gene that encodes LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both PWWP IN-binding domains are important LEDGF/p75 co-factor function. To assess role HRP2 integration, cells generated from Hdgfrp2 HRP2)...
Abstract There are an urgent need for antivirals to treat the newly emerged SARS-CoV-2. To identify new candidates we screened a repurposing library of ~3,000 drugs. Screening in Vero cells found few antivirals, while screening human Huh7.5 validated 23 diverse antiviral Extending our studies lung epithelial cells, that there major differences drug sensitivity and entry pathways used by SARS-CoV-2 these cells. Entry Calu-3 is pH-independent requires TMPRSS2, low pH triggering acid-dependent...
The novel coronavirus SARS-CoV-2 emerged in China at the end of 2019 and rapidly became a global pandemic. While there are variety experimental treatments currently clinical trials, is dearth approved therapeutics to treat COVID-19. Drug repurposing identifies existing that have already been through testing humans for new indications, particularly advantageous since they could be readily deployed. To this end, we screened library ~3,000 drugs their antiviral activity against cell-based...
Neurotropic viruses are the most common cause of infectious encephalitis and highly target neurons for infection. Our understanding intrinsic capacity neuronal innate immune responses to mediate protective antiviral remains incomplete. Here, we evaluated role intercellular crosstalk in mediating immunity its contribution limiting viral We found that absence antagonism, transcriptionally induce robust interferon signaling can effectively signal uninfected bystander neurons. Yet,...
Zika virus (ZIKV) can be transmitted by mosquito bite or sexual contact. Using mice that lack the type I interferon receptor, we examined transmission of ZIKV. Electron microscopy analyses showed association virions with developing sperm within testes as well mature epididymis. When ZIKV-infected male were mated naive female mice, weight fetuses at embryonic day 18.5 was significantly reduced compared control group. Additionally, found ocular deformities in a minority fetuses. These results...
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD) dimer interface occupying principal binding pocket its cellular cofactor LEDGF/p75. Consequently, inhibit interaction with LEDGF/p75 as well promote aberrant multimerization. Selection viral strains emerging under inhibitor pressure has revealed mutations near site. We have investigated effects one most prevalent substitutions, H171T IN,...
The DNA cutting and joining reactions of HIV-1 integration are catalyzed by integrase (IN), a viral protein that functions as tetramer bridging the two ends (intasome). Two major obstacles for biochemical structural studies intasomes 1) low efficiency assembly with oligonucleotide substrates, 2) non-specific aggregation both free IN in reaction mixture. By fusing small binding protein, Sulfolobus solfataricus chromosomal Sso7d (PDB: 1BNZ), we have engineered highly soluble hyperactive IN....
Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). While its central role in Disease 2019 (COVID-19) pathogenesis indisputable, there remains significant debate regarding of this transmembrane carboxypeptidase disease course. These include soluble versus membrane-bound ACE2, as well ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires vivo models. Here, we report...
Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs other TLRs is unknown. Here we show that RNA sensor TLR7. TLR7 present on red cell membrane associated with RBC protein Band 3. In patients SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in are increased when compared healthy controls. vitro, synthetic ssRNA from viruses. Thus, may serve as a previously unrecognized sink for exogenous RNA,...